Imidazoquinoxaline Src-Family Kinase p56(Lck) Inhibitors: SAR, QSAR, and the Discovery of (S)-N-(2-Chloro-6-methylphenyl)-2-(3-methyl-1-piperazinyl)imidazo- (1,5-a)pyrido(3,2-e)pyrazin-6-amine (BMS-279700) as a Potent and Orally Active Inhibitor with

摘要

A series of novel anilino 5-azaimidazoquinoxaline analogues possessing potent in vitro activity against p56(Lck) and T cell proliferation have been discovered. Subsequent SAR studies led to the identification of compound 4 (BMS-279700) as an orally active lead candidate that blocks the production of proinflammatory cytokines (IL-2 and TNFalpha) in vivo. In addition, an expanded set of imidazoquinoxalines provided several descriptive QSAR models highlighting the influence of significant steric and electronic features. The H-bonding (Met319) contribution to observed binding affinities within a tightly congeneric series was found to be significant.